Introduction

Mark Mattson is one of the researchers whose work I deeply admire and follow closely. He’s in the Department of Neurosciences at the National Institute on Aging. I wrote about his research on intermittent fasting and hormesis in my third book.

A recent article on neurohormetic phytochemicals [1] was published under his name in the journal Neurochemistry International. Let’s see what it’s about.

Neurowhat?

The word hormetic refers to a beneficial stressors; so neurohormetic is about beneficial stressors that act on the brain; phytochemicals are plant secondary metabolites. The authors of the study explain this better [1]:

Plants synthesize secondary metabolites, broadly termed ‘phytochemicals’ as defenses to dissuade insects and other herbivores from eating them. Most of these phytochemicals, which are usually bitter in taste, are present at a relatively low level in the plant materials. The co-evolution of plants and animals enabled adaptation of animals to these otherwise potentially toxic substances.

At low doses, phytochemicals have beneficial or stimulatory effects on animal cells, whereas when consumed in high amounts the phytochemicals can be toxic. This is an example of “hormesis” – when cells and organisms are challenged with mild stress by some of the noxious phytochemicals present in the plants, they respond adaptively in ways that help them withstand more severe stress.

When ingested, these phytochemicals activate adaptive stress response signaling pathways like SIRT1, AMPk, FOXO, NFκB, NRF2-ARE, MAPk, and others, while inhibiting pathways like IGF-1 and mTOR, and several others. This may lead to increased cellular resistance to injury and disease. Read this paper for an elegant description of the mechanism of neurohormesis and how it is activated by phytochemicals [3]. I will briefly discuss a few of these pathways.

SIRT1

This enzyme deacetylases proteins contributing to cellular regulatory processes (wiki). Deacetylases are a class of enzymes that remove acetyl groups from histones, cytosolic enzymes, as well as transcriptional factors; the effect is silencing of gene expression.

According to the authors, this pathway is often activated by calorie restriction (or IF + CR), exercise, and some phytochemicals. Upon activation [1]:

The substrates of SIRT1 include the tumor suppressor protein p53, Ku70 and forkhead box proteins (FOXO), which upon deacetylation confer resistance to cellular stress by mediating DNA repair, autophagy and apoptosis.

Mattson and Murugaiyah (2015) [1] think that sirtuins may mediate the tolerance to stress and may counteract the aging processes as well as the development of diseases such as CVD, diabetes, obesity, and neurodegenerative diseases.

One of the most researched molecules to activate SIRT1 and its ortholog genes (genes with similar function) in other species is resveratrol, a phytochemical commonly found in red wine. David Sinclair was the first to show how resveratrol is a CR mimetic and can increase lifespan in yeast [4].

There is increasing evidence on the positive effects of resveratrol on the human body. Timmers and colleagues (2011) did a 30-day randomized double-blind crossover trial where they administered 150mg/day of resveratrol to obese subjects. They observed lower resting metabolic rate, lower inflammation markers, and reduced sleeping requirements, as well as increasing levels of AMPk, SIRT1, and PGC-1α in their muscles [5]. Looking forward to see more of these studies with human subjects.

AMPk is often activated at the same time with SIRT1 (there is a positive feedback loop between them). When cellular energy is low – at higher (AMP+ADP)/ATP, AMPk is activated to restore NAD+ levels to higher values. From the authors [1]:

AMPK directly regulates mammalian FOXO3, a transcription factor known to promote resistance to oxidative stress, inhibit tumor cell survival, and promote longevity. AMPK is also emerging as a key nutrient-sensitive signaling protein that contributes to lifespan extension by energy restriction.

Calorie restriction, intermittent fasting, ketogenic diets (even non-CR regimens), alpha-lipoic acid, metformin and some of the phytochemicals mentioned above have been shown to increase the activation of AMPk.

mTOR – Mammalian Target of Rapamycin

This pathway is mostly involved in cell growth and it is influenced by amino acid (protein) availability. According to Mattson and Murugaiyah (2015):

Inhibiting mTOR in different model organisms has been shown to counteract the aging process through various mechanisms. I wrote about this extensively in Periodic Fasting. The activation of both AMPk and SIRT1 inhibits mTOR. One of the ways in which calorie restriction (CR) increases life span in different organisms is by suppressing TOR/mTOR pathways.

Some of the phytochemicals mentioned by Mattson to suppress TOR/mTOR (directly or indirectly through other mechanisms) are: turmeric/curcumin, EGCG, gartanin, pomegranate extract, and wogonin (found in Scuttellaria baicalensis – see above). However, calorie restriction and most importantly protein restriction will inhibit mTOR. It is best to inhibit the activity of this pathway in the context of uncontrolled/abnormal tissue/cell proliferation – tumors.

Feeding too much protein to a body that cannot handle it properly may lead to unwanted consequences and possible a shorter lifespan. Anecdotally (and not), most centenerian and supercentenerian populations (people who live past 100) consume low protein diets, taking their protein mostly from non-meat sources (eggs, dairy, and plant proteins).

IGF-1 – Insulin-like Growth Factor

This is another heavily studied pathway that’s been shown to play an important role in the rate of aging of different organisms (including humans). IGF-1 is often measured as a cancer predicting biomarker. Higher-levels => not good.

Under optimal circumstances – in growing organisms (i.e. children) increased IGF-1, mTOR, GH and several others pathways leads to a good development (maturing) of the subjects. However, when DNA is damaged and cellular repair mechanism are broken, and one activates IGF-1, insulin, and mTOR, the chances of abnormal cell proliferation are higher and this can lead to cancer formation.

As you could predict, calorie restriction, fasting, exercise, and several phytochemicals may lower the activity of the IGF-1 pathway. More simply, reducing insulin secretion will most likely reduce the activity of this pathway.

To learn more about healthy aging across different organisms, you can start with the overwhelming work of Valter Longo from The University of Southern California, currently also the Director of the Longevity Institute. I recommend this study, which is widely cited in the literature [6]. Then you can follow up by reading other studies under his name. Much of the inspiration to write my book Periodic Fasting was drawn from studies conducted by Valter Longo, Mark Mattson, as well as Luigi Fontana.

Here’s a sky-view of the pathways activated/inhibited by consuming phytochemical rich foods or supplements:

In this way, I aim toward making my body efficiently use the amount of protein I provide, instead of consuming too much and using it inefficiently. Consequently, with this approach I should be able to activate AMPk, SIRT1, FOXO and other repair/maintenance pathways while suppressing IIS (Insulin + IGF-1) and mTOR.

Moreover, for SIRT1 activation, I cyclically use a resveratrol supplement (~200mg/day) and consume red dry wine every now and then. In the future, when some supplements become cheaper I will use other (more efficient) NAD+ boosting supplements in conjunction with my multi-factorial approach.

For increased AMPk activation I cyclically use alpha-lipoic acid and EGCG extract. In the future, I may experiment with metformin, which was shown to increase AMPk activity and is currently under trial (TAME study – Targeting Aging with Metformin) as the first drug to increase healthy lifespan.

Some foods and supplements that I use (on an intermittent basis) are: allicin (from garlic extract), dark chocolate (85+ cocoa) which is rich in theobromine, brocolli and cabbage (loads of them, on a daily basis), curcumin, caffeine (black non-oiled, non-buttered coffee), citrus fruit paste/sauce, berries, and several others. For a more comprehensive list of supplements, please see this post.

If you have experience with other phytochemical rich foods or supplements, please let me know your thoughts in either of the comment sections below. I’d like to know what other folks use in their n=1 biohacking experiments.